$PROB BASE MODEL ;; Based on: 244 ;; 2. Description: ;; Original model ;; 3. Label: ;; EONLY1 ;; STUD in 1:2 only ;; 4. Structural model: ;; 2 comp PK + indirect PK with Bound compartment ;; 5. Covariate model: ;; No covariates ;; 6. Inter-individual variability: ;; CL, V, Q, V2, SAP10 ;; 7. Inter-occasion variability: ;; 8. Residual variability: ;; Proportional ;; 9. Estimation: ;; IMP $INPUT ID LABL=DROP AMT CHRT DV CRCL DURATION PERD RATE REGM=DROP TIME TRLD EVID MDV CMT STUD AMLOAD SEX AMLIVER ORD $DATA INPUTforEVAL.csv IGNORE=@ $SUBROUTINE ADVAN13 TOL9 $MODEL COMP=(PERIH1) COMP=(EFFECT) COMP=(PERIPH2) COMP=(PERIPH3) COMP=(SC) COMP=(COMP) $PK ;CPHPC MOLSAP = 5*25000*1000 ;; mg/mol (=Da*1000) MOLCPH = 340.37*1000 ;; mg/mol (=Da*1000) THRESH=80 IF(CRCL.GT.THRESH) THEN CRCL2 = THRESH ELSE CRCL2 = CRCL ENDIF CRCLEFF = ( 1 + THETA(15)*(CRCL2 - THRESH)) TVCL = CRCLEFF*EXP(THETA(2)) MU_2 = LOG(TVCL) CL = EXP(MU_2+ETA(2)) ;LTVV = THETA(3) TVV = EXP(THETA(3)) MU_3 = LOG(TVV) V = EXP(MU_3+ETA(3)) TVQ = EXP(THETA(4)) MU_4 = LOG(TVQ) Q = EXP(MU_4+ETA(4)) ;IF(CL.LT.Q) EXIT 1 101 TVV2 = EXP(THETA(5)) MU_5 = LOG(TVV2) V2 = EXP(MU_5+ETA(5)) TVK12 = Q/V K12 = TVK12 TVK21 = Q/V2 K21 = TVK21 K10=CL/V ;SAP TVV3 = V;EXP(THETA(16)) ; TVV V3 = TVV3 ;VP = 3 ;V3 = VP TVV4 = EXP(THETA(16)) MU_10 = LOG(TVV4) V4 = EXP(MU_10+ ETA(10)) ; 12 TVSAP10 = EXP(THETA(6)) MU_6 = LOG(TVSAP10) SAP10= EXP(MU_6+ETA(6)) TVKOUT = EXP(THETA(1)) MU_1 = LOG(TVKOUT) KOUT = EXP(MU_1+ETA(1)) TVKON = EXP(THETA(7)) MU_7 = LOG(TVKON) KON = EXP(MU_7+ETA(7)) ;;0.540 ;; L/h KD = 10*10**(-9) TVKOFF = TVKON*KD KOFF = TVKOFF TVKINT = THETA(8) MU_8 = LOG(TVKINT) KINT = EXP(MU_8+ETA(8)) TVQ4 = EXP(THETA(17)) MU_9 = LOG(TVQ4) Q4 = EXP(MU_9+ETA(9)) TVK34 = Q4/V3 K34 = TVK34 TVK43 = Q4/V4 K43 = TVK43 KIN = KOUT*(SAP10*V3) AM3 = SAP10/MOLSAP AM4 = SAP10/MOLSAP A_0(3)=AM3 A_0(4)=AM4 F1 = 1 F5 = THETA(13) TVKSC = EXP(THETA(14)) MU_11 = LOG(TVKSC) KSC = EXP(MU_11+ETA(11)) S1=V/(1000) S3=1/(1000*MOLSAP) $DES A1=A(1) A3=A(3) A2=A(2) A4=A(4) A5=A(5) A6=A(6) C1 = A1/(V*MOLCPH) C3 = A3 C3C1 = A6 C3C1_STD = C3C1*MOLCPH*V3 A1F = A1-C3C1_STD C3F = C3-C3C1 C1F = A1F/(V*MOLCPH) DADT1= -K10*A1F + KSC*A5 - K12*A1F + K21*A2 -KINT*(V*MOLCPH)*C3C1 ;; CPHPC (PLASMA) (mg) DADT2= K12*A1F - K21*A2 ;; CPHPC (PERIPH) (mg) DADT3= KIN/(V3*MOLSAP)-KOUT*C3F -KINT*C3C1 + K43*A4*V4/V3 - K34*C3F ;; SAP PLASMA conc (mol/L) DADT4= -K43*A4 + K34*C3F*V3/V4 ;; SAP PLASMA conc (mol/L) DADT5=-KSC*A5 DADT6= KON*C3F*C1F - (KINT)*C3C1 DADT(1) = DADT1 DADT(2) = DADT2 DADT(3) = DADT3 DADT(4) = DADT4 DADT(5) = DADT5 DADT(6) = DADT6 $ERROR ER1=ERR(1) ER2=ERR(2) IPRED = F IF (CMT.EQ.1) THEN W = THETA(9) W2 = THETA(10) Y1 = IPRED*(1+W*ER1) + W2*ER2 ELSE W=THETA(11) W2 = THETA(12) Y1 = IPRED*(1+W*ER1) + W2*ER2 ENDIF IF(IPRED.EQ.0) IPRED = 0.01 Y = Y1 IRES=DV-IPRED IWRES = IRES/(IPRED*W) $THETA -3.07 ; 1. KOUT 1.92 ; 2. CL 2.76 ; 3. V 0.595 ; 4. Q 2.84 ; 5. V2 3.37 ; 6. SAP10 14.6 ; 7. KON 5.71 ; 8. KINT (0,0.286) ; 9. PROPPK 0 FIX ; 10. ADDPK (0,0.268) ; 11. PROPSAP 0 FIX ; 12. ADDSAP (0,1) FIX ; 13. FSC 0.4055 FIX ; 14. KASC (-1,0.0152,0.6) ; 15. CRCLCOV 3.47 ; 16. V4 (-20,1.49,20) ; 17. Q4 $OMEGA 0.125 ; 1. OMKOUT 0.0474 ; 2. OMCL 0.0836 ; 3. OMV 0.0225 FIX ; 4. OMQ 0.0225 FIX ; 5. OMV2 0.0625 ; 6. OMSAP10 0.0225 FIX ; 7. OMKON 0.0225 FIX ; 8. OMKINT 1.11 ; 9. OMQ4 2.05 ; 10. OMV4 0.0225 FIX ; 11. OMKSC $SIGMA 1 FIX 1 FIX ;$EST METHOD=ITS INTER NITER=10 PRINT=1 CTYPE=1 CITER=10 GRD=DDDDDDDDSSSSDDDDD ;$EST METHOD=IMP INTER ISAMPLE=600 NITER=130 PRINT=1 CTYPE=1 CITER=10 CALPHA=0.01 GRD=DDDDDDDDSSSSDDDDD ;$EST MAXEVAL=9999 PRINT=5 POSTHOC METHOD=0 INTERACTION MSFO=msf NOABORT SIGL=9 NSIG=3 $EST METHOD=IMP INTER ISAMPLE=10000 NITER=5 EONLY=1 $COV UNCONDITIONAL PRINT=E SIGL=12 $TABLE ID CL V Q V2 KSC SAP10 KIN KOUT Q4 V4 KON KINT NOAPPEND NOPRINT ONEHEADER FILE=OUTPUTforEVAL.csv FORMAT=,1PE11.4f